Approximately 800,000 people die from suicide each year and the recent data show that the suicide rate in the United States has increased 33% from 1999 to 2017. United States military veterans have an increased risk of suicide compared with the general population, and approximately 18 to 22 veterans die from suicide each day. It has been reported that up to 90% of individuals who complete suicide have an underlying psychiatric disorder. Suicidal ideation in war veterans is often associated with post-traumatic disorder (PTSD) or depression, conditions that often coexist. In addition, as a fundamental factor in the provocation of depression, chronic stress is associated with suicidal thoughts and behaviors. Also, a history of prior exposure to trauma or to chronic stress is an extremely potent risk factor for PTSD. In preclinical models, chronic stress has been shown to induce changes in behavioral paradigms that can be used to measure aspects of suicidal behavior such as impulsive, aggressive, and depressive-like behaviors. Recent evidence indicate that inflammation, as manifested by increased levels of pro?inflammatory cytokines, contributes to the pathophysiology of suicidality. However, there is a critical need for studies that are designed to determine the role of specific components of the immune system in suicidal behavior in order to identify novel therapeutic targets. The complement system is part of the innate arm of immunity, but also regulates many aspects of the adaptive immune response. Complement can be activated via the classical, lectin or alternative pathway with complement component 3 (C3) as the converging point of the activation pathways. Our recent study showed an important role of C3 in chronic stress-induced depressive-like behavior in mice. However, it is not known whether chronic stress- induced complement activation mediates suicidal behavior. We hypothesize that classical pathway mediates stress-induced complement activation leading to suicidal behavior. In supporting this, our published and preliminary studies found that (1) C3 and C1qa (a key component of classical pathway) are highly expressed in the prefrontal cortex (PFC) of depressed suicide subjects; 2) exposure to chronic stress conditions induces increases in C1qa and C3 protein levels in mouse PFC; and (3) inhibition of C3 by gene knockout (C3 KO) significantly ameliorated chronic stress-induced aggressive and depressive-like behavior, and infiltration of monocytes into mouse PFC. To further understand the role of complement activation in suicidal behavior, we propose the three Specific Aims to 1) determine the role of complement activation pathway in suicide (with depression or PTSD diagnosis) subjects; 2) investigate whether complement classical pathway is critical to stress-induced suicidal behavior; and 3) determine whether central complement system mediates stress- induced suicidal behavior. Given the important role of immune pathways in suicidal behavior, identifying novel regulatory mechanisms may provide avenues to develop newer therapeutics for suicidal behavior.